Suitability of digoxin as a P‐glycoprotein probe: Implications of other transporters on sensitivity and specificity

The study of transporter‐mediated drug–drug interactions (DDI) requires use of appropriate probes to reflect transporter function. Digoxin is often used as a probe in DDI studies involving P‐glycoprotein (P‐gp) and is recommended by FDA for this purpose, despite several lingering questions regarding suitability of digoxin as P‐gp probe. This review aims to critically evaluate use of digoxin as a probe for P‐gp‐mediated clinical DDI studies, with focus on sensitivity and specificity of digoxin for P‐gp. Although previous reviews have evaluated digoxin transport by P‐gp, the purpose of the current review is to critically evaluate such literature in light of newly evolving literature suggesting digoxin transport by non‐P‐gp transporters.

[1]  R. B. Parker,et al.  Effects of Grapefruit Juice on Intestinal P‐glycoprotein: Evaluation Using Digoxin in Humans , 2003, Pharmacotherapy.

[2]  Y. Sawada,et al.  Influence of SLCO1B3 gene polymorphism on the pharmacokinetics of digoxin in terminal renal failure. , 2008, Drug metabolism and pharmacokinetics.

[3]  Miyuki Kimura,et al.  Role of human MDR1 gene polymorphism in bioavailability and interaction of digoxin, a substrate of P‐glycoprotein , 2002, Clinical pharmacology and therapeutics.

[4]  P. Borst,et al.  Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. , 1995, The Journal of clinical investigation.

[5]  M. Pirmohamed,et al.  ABCB1 single nucleotide polymorphisms (1236C>T, 2677G>T, and 3435C>T) do not affect transport activity of human P-glycoprotein , 2013, Pharmacogenetics and genomics.

[6]  D. B. Duignan,et al.  Characterization of Digoxin Uptake in Sandwich-Cultured Human Hepatocytes , 2011, Drug Metabolism and Disposition.

[7]  R. Kim,et al.  Transporters and drug therapy: Implications for drug disposition and disease , 2005, Clinical pharmacology and therapeutics.

[8]  J. Beijnen,et al.  Full blockade of intestinal P-glycoprotein and extensive inhibition of blood-brain barrier P-glycoprotein by oral treatment of mice with PSC833. , 1997, The Journal of clinical investigation.

[9]  T. Futami,et al.  Organic Anion Transporter oatp2-Mediated Interaction between Digoxin and Amiodarone in the Rat Liver , 2002, Pharmaceutical Research.

[10]  Seymour Reichlin,et al.  Handbook of experimental pharmacology , 1984 .

[11]  T. Beveridge,et al.  Absolute bioavailability of digoxin tablets. , 1978, Arzneimittel-Forschung.

[12]  M Zschiesche,et al.  Oral bioavailability of digoxin is enhanced by talinolol: Evidence for involvement of intestinal P‐glycoprotein , 2000, Clinical pharmacology and therapeutics.

[13]  Patrick Marroum,et al.  Mechanistic analysis of solute transport in an in vitro physiological two‐phase dissolution apparatus , 2012 .

[14]  I. Tamai,et al.  Physiologically based pharmacokinetics of digoxin in mdr1a knockout mice. , 1999, Journal of pharmaceutical sciences.

[15]  Yan Zhang,et al.  The relevance of assessment of intestinal P-gp inhibition using digoxin as an in vivo probe substrate , 2010, Nature Reviews Drug Discovery.

[16]  M. Cavet,et al.  Evidence for a non-MDR1 component in digoxin secretion by human intestinal Caco-2 epithelial layers. , 2003, European journal of pharmacology.

[17]  Leslie Z. Benet,et al.  Ex Situ Inhibition of Hepatic Uptake and Efflux Significantly Changes Metabolism: Hepatic Enzyme-Transporter Interplay , 2004, Journal of Pharmacology and Experimental Therapeutics.

[18]  Kazuya Maeda,et al.  PREDOMINANT CONTRIBUTION OF OATP1B3 TO THE HEPATIC UPTAKE OF TELMISARTAN, AN ANGIOTENSIN II RECEPTOR ANTAGONIST, IN HUMANS , 2006, Drug Metabolism and Disposition.

[19]  P. Olinga,et al.  Characterization of the uptake of rocuronium and digoxin in human hepatocytes: carrier specificity and comparison with in vivo data. , 1998, The Journal of pharmacology and experimental therapeutics.

[20]  Mitchell E Taub,et al.  Digoxin Is Not a Substrate for Organic Anion-Transporting Polypeptide Transporters OATP1A2, OATP1B1, OATP1B3, and OATP2B1 but Is a Substrate for a Sodium-Dependent Transporter Expressed in HEK293 Cells , 2011, Drug Metabolism and Disposition.

[21]  Joseph D. Ma,et al.  Evaluation of In Vivo P-Glycoprotein Phenotyping Probes , 2010, Clinical pharmacokinetics.

[22]  H. Glaeser.  Importance of P-glycoprotein for drug-drug interactions. , 2011, Handbook of experimental pharmacology.

[23]  P. Meier,et al.  Isolation of a multispecific organic anion and cardiac glycoside transporter from rat brain. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[24]  L J Lesko,et al.  Drug Interaction Studies: Study Design, Data Analysis, and Implications for Dosing and Labeling , 2007, Clinical pharmacology and therapeutics.

[25]  J. Sahi,et al.  Determination of OATP-, NTCP- and OCT-mediated substrate uptake activities in individual and pooled batches of cryopreserved human hepatocytes. , 2011, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[26]  M. Cavet,et al.  Transport and epithelial secretion of the cardiac glycoside, digoxin, by human intestinal epithelial (Caco‐2) cells , 1996, British journal of pharmacology.

[27]  P. Sexton,et al.  Drug transporters in drug efficacy and toxicity. , 2012, Annual review of pharmacology and toxicology.

[28]  J. Polli,et al.  Kinetic Identification of Membrane Transporters That Assist P-glycoprotein-Mediated Transport of Digoxin and Loperamide through a Confluent Monolayer of MDCKII-hMDR1 Cells , 2008, Drug Metabolism and Disposition.

[29]  W. L. Chiou,et al.  The complexity of intestinal absorption and exsorption of digoxin in rats. , 2006, International journal of pharmaceutics.

[30]  H. Glaeser,et al.  P‐glycoprotein‐mediated intestinal and biliary digoxin transport in humans , 2003, Clinical pharmacology and therapeutics.

[31]  Lalitha Podila,et al.  FUNCTIONAL ASSESSMENT OF MULTIPLE P-GLYCOPROTEIN (P-GP) PROBE SUBSTRATES: INFLUENCE OF CELL LINE AND MODULATOR CONCENTRATION ON P-GP ACTIVITY , 2005, Drug Metabolism and Disposition.

[32]  Y. Cheung,et al.  Meta-analysis of the influence of MDR1 C3435T polymorphism on digoxin pharmacokinetics and MDR1 gene expression. , 2005, British journal of clinical pharmacology.

[33]  J. Crison,et al.  A Theoretical Basis for a Biopharmaceutic Drug Classification: The Correlation of in Vitro Drug Product Dissolution and in Vivo Bioavailability , 1995, Pharmaceutical Research.

[34]  Piet Borst,et al.  Substantial excretion of digoxin via the intestinal mucosa and prevention of long‐term digoxin accumulation in the brain by the mdrla P‐glycoprotein , 1996, British journal of pharmacology.

[35]  M. Roberts,et al.  Kinetic analysis of saturable hepatic uptake of digoxin and its inhibition by rifampicin. , 2008, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[36]  Y. Tanigawara,et al.  Transport of digoxin by human P-glycoprotein expressed in a porcine kidney epithelial cell line (LLC-PK1). , 1992, The Journal of pharmacology and experimental therapeutics.

[37]  M. Roberts,et al.  An Improved Nonlinear Model Describing the Hepatic Pharmacokinetics of Digoxin: Evidence for Two Functionally Different Uptake Systems and Saturable Binding , 2010, Pharmaceutical Research.

[38]  G R Wilkinson,et al.  Inhibition of P-glycoprotein-mediated drug transport: A unifying mechanism to explain the interaction between digoxin and quinidine [seecomments]. , 1999, Circulation.

[39]  Toshinori Yamamoto,et al.  Ribosomal protein L3 mediated the transport of digoxin in Xenopus laevis oocyte. , 2010, The Journal of toxicological sciences.

[40]  K. Schenck-Gustafsson,et al.  Digoxin‐verapamil interaction: Reduction of biliary but not renal digoxin clearance in humans , 1991, Clinical pharmacology and therapeutics.

[41]  Leslie Z Benet,et al.  The drug transporter-metabolism alliance: uncovering and defining the interplay. , 2009, Molecular pharmaceutics.

[42]  L Landmann,et al.  Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. , 2001, Gastroenterology.

[43]  T. Murakami,et al.  Role of organic anion transporting polypeptide 2 in pharmacokinetics of digoxin and beta-methyldigoxin in rats. , 2005, Journal of Pharmacy and Science.

[44]  H. Takane,et al.  The MDR1 (ABCB1) Gene Polymorphism and its Clinical Implications , 2004, Clinical pharmacokinetics.

[45]  Christopher J Endres,et al.  The role of transporters in drug interactions. , 2006, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[46]  T. Abe,et al.  Isolation and characterization of a digoxin transporter and its rat homologue expressed in the kidney. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[47]  W. Jusko,et al.  Pharmacokinetics of digoxin in normal subjects after intravenous bolus and infusion doses , 1975, Journal of Pharmacokinetics and Biopharmaceutics.

[48]  U. Hofmann,et al.  Increased Absorption of Digoxin from the Human Jejunum Due to Inhibition of Intestinal Transporter-Mediated Efflux , 2007, Clinical pharmacokinetics.

[49]  W. Haefeli,et al.  Substantial pharmacokinetic interaction between digoxin and ritonavir in healthy volunteers , 2004, Clinical pharmacology and therapeutics.

[50]  U. Brinkmann,et al.  Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[51]  H K Kroemer,et al.  The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin. , 1999, The Journal of clinical investigation.